The overall goal is the reliable identification of genes that are important in the general population in predisposing to serious common diseases such as cancer, heart disease, or diabetes. The basic hypothesis is that a substantial fraction of all genes that predispose the heterozygous carrier to a particular common disease may be identified because the same gene causes in homozygotes a distinctive autosomal recessive syndrome. Identifying these specific genes is an important first step in understanding their metabolic action and in clarifying gene-environment interactions that produce clinical disease. To measure the disease predisposition of heterozygous carriers for selected autosomal recessive syndromes, disease incidence or mortality among close blood relatives, including obligatory heterozygotes, is compared to that of spouse controls within the same families. Because of substantial earlier interest in the finding that ataxia-telangiectasia (A-T) heterozygotes had an excess risk of cancer, and of new findings concerning diabetes and heart disease risk, a group of more than 150 families has been assembled for prospective observation during this project period. New retrospective studies of diabetes incidence in families with the Wolfram syndrome or with hemochromatosis are planned to test the hypothesis, based on earlier observations, that the heterozygous carrier for each of these genes may be predisposed to diabetes. The gene for hemochromatosis is of interest because of its estimated high gene frequency in most populations and the feasibility of evaluating the diabetes predisposition of heterozygotes through case-control studies, using direct identification of carriers within families by means of the linkage relationship between the hemochromatosis gene and the HLA locus.